A small molecule that binds to an ATPase domain of Hsc70 promotes membrane trafficking of mutant cystic fibrosis transmembrane conductance regulator.

DC Field

Value

Language

dc.contributor.author

이민구

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dc.date.accessioned

2014-12-20T17:30:06Z

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dc.date.available

2014-12-20T17:30:06Z

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dc.date.issued

2011

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dc.identifier.issn

0002-7863

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dc.identifier.uri

https://ir.ymlib.yonsei.ac.kr/handle/22282913/94718

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dc.description.abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) is a cell-surface anion channel that permeates chloride and bicarbonate ions. The most frequent mutation of CFTR that causes cystic fibrosis is the deletion of phenylalanine at position 508 (ΔF508), which leads to defects in protein folding and cellular trafficking to the plasma membrane. The lack of the cell-surface CFTR results in a reduction in the lifespan due to chronic lung infection with progressive deterioration of lung function. Hsc70 plays a crucial role in degradation of mutant CFTR by the ubiquitin-proteasome system. To date, various Hsc70 inhibitors and transcription regulators have been tested to determine whether they correct the defective activity of mutant CFTR. However, they exhibited limited or questionable effects on restoring the chloride channel activity in cystic fibrosis cells. Herein, we show that a small molecule apoptozole (Az) has high cellular potency to promote membrane trafficking of mutant CFTR and its chloride channel activity in cystic fibrosis cells. Results from affinity chromatography and ATPase activity assay indicate that Az inhibits the ATPase activity of Hsc70 by binding to its ATPase domain. In addition, a ligand-directed protein labeling and molecular modeling studies also suggest the binding of Az to an ATPase domain, in particular, an ATP-binding pocket. It is proposed that Az suppresses ubiquitination of ΔF508-CFTR maybe by blocking interaction of the mutant with Hsc70 and CHIP, and, as a consequence, it enhances membrane trafficking of the mutant.

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dc.description.statementOfResponsibility

open

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dc.format.extent

20267~20276

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dc.relation.isPartOf

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

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dc.rights

CC BY-NC-ND 2.0 KR

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dc.rights.uri

https://creativecommons.org/licenses/by-nc-nd/2.0/kr/

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dc.subject.MESH

Adenosine Triphosphatases/chemistry

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dc.subject.MESH

Adenosine Triphosphatases/metabolism*

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dc.subject.MESH

Benzamides/chemistry

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dc.subject.MESH

Benzamides/metabolism*

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dc.subject.MESH

Binding Sites

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dc.subject.MESH

Cell Line

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dc.subject.MESH

Cystic Fibrosis Transmembrane Conductance Regulator/genetics

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dc.subject.MESH

Cystic Fibrosis Transmembrane Conductance Regulator/metabolism*

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dc.subject.MESH

HSC70 Heat-Shock Proteins/metabolism*

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dc.subject.MESH

Humans

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dc.subject.MESH

Imidazoles/chemistry

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dc.subject.MESH

Imidazoles/metabolism*

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dc.subject.MESH

Magnetic Resonance Spectroscopy

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dc.subject.MESH

Mutation*

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dc.subject.MESH

Protein Transport

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dc.subject.MESH

Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

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dc.subject.MESH

Ubiquitination

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dc.title

A small molecule that binds to an ATPase domain of Hsc70 promotes membrane trafficking of mutant cystic fibrosis transmembrane conductance regulator.

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dc.type

Article

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dc.contributor.college

College of Medicine (의과대학)

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dc.contributor.department

Dept. of Pharmacology (약리학)

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dc.contributor.googleauthor

Hyungseoph J. Cho

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dc.contributor.googleauthor

Heon Yung Gee

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dc.contributor.googleauthor

Kyung-Hwa Baek

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dc.contributor.googleauthor

Sung-Kyun Ko

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dc.contributor.googleauthor

Jong-Moon Park

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dc.contributor.googleauthor

Hookeun Lee

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dc.contributor.googleauthor

Nam-Doo Kim

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dc.contributor.googleauthor

Min Goo Lee

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dc.contributor.googleauthor

Injae Shin

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dc.identifier.doi

10.1021/ja206762p

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dc.admin.author

false

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dc.admin.mapping

false

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dc.contributor.localId

A02781

-

dc.contributor.localId

A03971

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dc.relation.journalcode

J01769

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dc.identifier.eissn

1520-5126

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dc.identifier.pmid

22074182

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dc.identifier.url

http://pubs.acs.org/doi/abs/10.1021/ja206762p

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dc.contributor.alternativeName

Lee, Min Goo

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dc.contributor.affiliatedAuthor

Lee, Min Goo

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dc.contributor.affiliatedAuthor

Gee, Heon Yung

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dc.rights.accessRights

not free

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dc.citation.volume

133

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dc.citation.number

50

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dc.citation.startPage

20267

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dc.citation.endPage

20276

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dc.identifier.bibliographicCitation

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol.133(50) : 20267-20276, 2011